F. M. Singer et al., Proc. Soc. Exper. Biol. Med., 102, 370 (1959) and F. H. Hulcher, Arch. Biochem. Biophys., 146, 422 (1971) disclose that certain mevalonate derivatives inhibit the biosynthesis of cholesterol.
Endo et al in U.S. Pat. Nos. 4,049,495, 4,137,322 and 3,983,140 disclose a fermentation product which is active in the inhibition of cholesterol biosynthesis. This product is called compactin and was reported by Brown et al., (J. Chem. Soc. Perkin I. 1165 (1976)) to have a complex mevalonolactone structure.
GB 1,586,152 discloses a group of synthetic compounds of the formula ##STR2## in which E represents a direct bond, a C.sub.1-3 alkylene bridge or a vinylene bridge and the various R's represent a variety of substituents.
The activity reported in the U.K. patent is less than 1% that of compactin.
U.S. Pat. No. 4,375,475 to Willard et al discloses hypocholesterolemic and hypolipemic compounds having the structure ##STR3## wherein A is H or methyl; E is a direct bond, --CH.sub.2 --, --CH.sub.2 --CH.sub.2 --, --CH.sub.2 --CH.sub.2 --CH.sub.2 -- or --CH.dbd.CH--; R.sub.1, R.sub.2 and R.sub.3 are each selected from H, halogen, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, phenyl, phenyl substituted by halogen, C.sub.1-4 alkoxy, C.sub.2-8 alkanoyloxy, C.sub.1-4 alkyl, or C.sub.1-4 haloalkyl, and OR.sub.4 in which R.sub.4 is H, C.sub.2-8 alkanoyl, benzoyl, phenyl, halophenyl, phenyl C.sub.1-3 alkyl, C.sub.1-9 alkyl, cinnamyl, C.sub.1-4 haloalkyl, allyl, cycloalkyl-C.sub.1-3 -alkyl, adamantyl-C.sub.1-3 -alkyl, or substituted phenyl C.sub.1-3 -alkyl in each of which the substituents ar selected from halogen, C.sub.1-4 alkoxy, C.sub.1-4 alkyl, or C.sub.1-4 haloalkyl; and the corresponding dihydroxy acids resulting from the hydrolytic opening of the lactone ring, and the pharmaceutically acceptable salts of said acids, and the C.sub.1-3 alkyl and phenyl, dimethylamino or acetylamino substituted C.sub.1-3 -alkyl esters of the dihydroxy acids; all of the compounds being the enantiomers having a 4 R configuration in the tetrahydropyran moiety of the trans racemate shown in the above formula.
WO 84/02131 (PCT/EP83/00308) (based on U.S. application Ser. No. 443,668, filed Nov. 22, 1982, and U.S. application Ser. No. 548,850, filed Nov. 4, 1983), filed in the name of Sandoz AG discloses heterocyclic analogs of mevalono lactone and derivatives thereof having the structure ##STR4## wherein one of R and R.sub.o is ##STR5## and the other is primary or secondary C.sub.1-6 alkyl, C.sub.3-6 cycloalkyl or phenyl-(CH.sub.2).sub.m --,
wherein R.sub.4 is hydrogen, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, (except t-butoxy), trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy,
R.sub.5 is hydrogen, C.sub.1-3 alkyl, C.sub.1-3 alkoxy, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy,
R.sub.5a is hydrogen, C.sub.1-2 alkyl, C.sub.1-2 alkoxy, fluoro or chloro, and
m is 1, 2 or 3
with the provisos that both R.sub.5 and R.sub.5a must be hydrogen when R.sub.4 is hydrogen, R.sub.5a must be hydrogen when R.sub.5 is hydrogen, not more than one of R.sub.4 and R.sub.5 is trifluoromethyl, not more than one of R.sub.4 and R.sub.5 is phenoxy and not more than one of R.sub.4 and R.sub.5 is benzyloxy,
R.sub.2 is hydrogen, C.sub.1-4 alkyl, C.sub.3-6 cycloalkyl, C.sub.1-4 alkoxy (except t-butoxy), trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy,
R.sub.3 is hydrogen, C.sub.1-3 alkyl, C.sub.1-3 alkoxy, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy, with the provisos that R.sub.3 must be hydrogen when R.sub.2 is hydrogen, not more than one of R.sub.2 and R.sub.3 is trifluoromethyl, not more than one of R.sub.2 and R.sub.3 is phenoxy, and not more than one of R.sub.2 and R.sub.3 is benzyloxy. ##STR6## wherein R.sub.6 is hydrogen or C.sub.1-3 alkyl in free acid form or in the form of a physiologically-hydrolysable and -acceptable ester or a .delta. lactone thereof or in salt form.
GB 2162-179-A discloses naphthyl analogues of mevalolactone useful as cholesterol biosynthesis inhibitors having the structure ##STR7## wherein R.sub.1 =1-3C alkyl;
Z is a gp. of formula Z.sub.1 or Z.sub.2 : ##STR8##
R.sub.7 =H, a hydrolysable ester gp. or a cation.
European Patent No. 164-698-A discloses preparation of lactones useful as anti-hyper-chloresterolemic agents by treating an amide with an organic sulphonyl halide R.sup.5 SO.sub.2 X, then removing the protecting group Pr. ##STR9## wherein X=halo; PR=a carbinol-protecting group;
R.sup.1 =H or CH.sub.3 ; PA1 R.sup.3, R.sup.4 =H, 1-3C alkyl or phenyl-(1-3C alkyl), the phenyl being optionally substituted by 1-3C alkyl, 1-3C alkoxy or halo; PA1 R.sup.2 =a group of formula (A) or (B): ##STR10## R.sup.6 =H or OH; R=H or CH.sub.3 ; PA1 a, b, c and d=optional double bonds; PA1 R.sup.7 =phenyl or benzyloxy, the ring in each case being optionally substituted by 1-3C alkyl or halo; PA1 R.sup.8, R.sup.9 =1-3C alkyl or halo; PA1 R.sup.5 =1-3C alkyl, phenyl or mono- or di-(1-3C alkyl)phenyl. PA1 or R+R.sub.1 =(CH.sub.2).sub.m or (Z)--CH.sub.2 --CH.dbd.CH--CH.sub.2 ; PA1 m=2-6; PA1 R.sub.o =1-6C alkyl, 3-7C cycloalkyl or R.sub.4, R.sub.5, R.sub.6 -substituted phenyl; PA1 R.sub.2 and R.sub.3 =H, Cl, Br, CN, CF.sub.3, phenyl, 1-4C alkyl, 2-8C carboalkoxy, --CH.sub.2 OR.sub.6 or --CH.sub.2 OCONHR.sub.7 ; PA1 E is --CH.sub.2 CH.sub.2, --CH.dbd.CH--, or --(CH.sub.2).sub.r --; and PA1 Z is 1) ##STR34## wherein X is --O-- or --NR.sup.9 wherein R.sup.9 is hydrogen or C.sub.1-3 alkyl; PA1 R.sup.7 is C.sub.2-8 alkyl; and PA1 R.sup.8 is hydrogen or CH.sub.3 ; 27 ##STR35## wherein R.sup.10, R.sup.11 and R.sup.12 are independently, e.g., hydrogen, halogen or C.sub.1-4 alkyl; ##STR36## wherein n is 0-2 and R.sup.14 is halo or C.sub.1-4 alkyl; or 4) ##STR37## PA1 X is CH.sub.2, --CH.sub.2 CH.sub.2 --, --CH.sub.2 CH.sub.2 CH.sub.2 --, --CH.dbd.CH--, --C.tbd.C-- or --CH.sub.2 O-- (where O is linked to Z); PA1 Z is a hydrophobic anchor;
Anderson, Paul Leroy, Ger. Offen. DE 3,525,256 discloses naphthyl analogs of mevalonolactones of the structure ##STR11## wherein R.sup.1 is alkyl, Z=Q, Q.sup.1 ; R.sup.7 ; H, or a hydrolyzable ester group useful as inhibitors of cholesterol biosynthesis and in treatment of atherosclerosis.
WO 8402-903 (based on U.S. application Ser. No. 460,600, filed Jan. 24, 1983) filed in the name of Sandoz AG discloses mevalono-lactone analogues useful as hypolipoproteinaemic agents having the structure ##STR12## wherein the two groups Ro together form a radical of formula ##STR13##
wherein R.sub.2 is hydrogen, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, (except t-butoxy), trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy,
R.sub.3 is hydrogen, C.sub.1-3 alkyl, C.sub.1-3 alkoxy, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy, with the provisos that not more than one of R.sub.2 and R.sub.3 is trifluoromethyl, not more than one of R.sub.2 and R.sub.3 is phenoxy, and not more than one of R.sub.2 and R.sub.3 is benzyloxy,
R.sub.1 is hydrogen, C.sub.1-6 alkyl, fluoro, chloro or benzyloxy,
R.sub.4 is hydrogen, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, (except t-butoxy), trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy,
R.sub.5 is hydrogen, C.sub.1-3 alkyl, C.sub.1-3 alkoxy, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy,
R.sub.5a is hydrogen, C.sub.1-2 alkyl, C.sub.1-2 alkoxy, fluoro or chloro, and with the provisos that not more than one of R.sub.4 and R.sub.5 is trifluoromethyl, not more than one of R.sub.4 and R.sub.5 is phenoxy and not more than one of R.sub.4 and R.sub.5 is benzyloxy, ##STR14## wherein n is 0, 1, 2 or 3 and both q's are 0 or one is 0 and the other is 1, ##STR15##
wherein R.sub.6 is hydrogen or C.sub.1-3 alkyl, with the general proviso that -X-Z and the R.sub.4 bearing phenyl group are ortho to each other;
in free acid form or in the form of a physiologically-hydrolysable and acceptable ester or a .delta. lactone thereof or in salt form.
U.S. Pat. No. 4,613,610 to Wareing (assigned to Sandoz) discloses a series of 7-pyrazolo-3,5-dihydrohept-6-enoic acid HMG-CoA reductase inhibitors of the structure ##STR16## wherein
R.sub.1 is C.sub.1-6 alkyl not containing an asymmetric carbon atom,
each of R.sub.2 and R.sub.5 is independently hydrogen, C.sub.1-3 alkyl, n-butyl, i-butyl, t-butyl, C.sub.1-3 alkoxy, n-butoxy, i-butoxy, trifluoromethyl, fluoro, chloro, phenyl, phenoxy or benzyloxy,
each of R.sub.3 and R.sub.6 is independently hydrogen, C.sub.1-3 alkyl, C.sub.1-3 alkoxy, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy,
each of R.sub.4 and R.sub.7 is independently hydrogen, C.sub.1-2 alkyl, C.sub.1-2 alkoxy, fluoro or chloro, with the provisos that not more than one of R.sub.2 and R.sub.3 is trifluoromethyl, not more than one of R.sub.2 and R.sub.3 is phenoxy, not more than one of R.sub.2 and R.sub.3 is benzyloxy, not more than one of R.sub.5 and R.sub.6 is trifluoromethyl, not more than one of R.sub.5 and R.sub.6 is phenoxy, and not more than one of R.sub.5 and R.sub.6 is benzyloxy,
X is --(CH.sub.2).sub.m --, --CH.dbd.CH--, --CH.dbd.CH--CH.sub.2 -or --CH.sub.2 --CH.dbd.CH--, wherein m is 0, 1, 2 or 3, and Z is ##STR17## wherein R.sub.10 is hydrogen or C.sub.1-3 alkyl, and R.sub.11 is hydrogen, R.sub.12 or M, wherein
R.sub.12 is a physiologically acceptable and hydrolyzable ester group, and
M is a cation,
with the provisos that (i) the -X-Z group is in the 4- or 5-position of the pyrazole ring, and (ii) the R.sub.1 group and the -X-Z group are ortho to each other.
WO 8607-054A (Sandoz-Erfindungen) discloses imidazole analogues of mevalonolactone, useful for treating hyperlipoproteinaemia and atherosclerosis, which have the formula ##STR18##
R.sub.1 =alkyl, cycloalkyl, adamantyl-1 or R.sub.4, R.sub.5, R.sub.6 -substituted phenyl (gp. A);
R.sub.2 =alkyl, cycloalkyl, adamantyl-1 or R.sub.7, R.sub.8, R.sub.9 - substituted phenyl (gp. B);
R.sub.3 =H, alkyl, cycloalkyl, adamantyl-1, styryl or R.sub.10, R.sub.11, R.sub.12 -substituted phenyl (gp, C);
X=--(CH.sub.2).sub.m --, --CH.dbd.CH--, --CH.dbd.CH--CH.sub.2 -- or --CH.sub.2 --CH.dbd.CH--;
m=0-3;
Z=--CH(OH)--CH.sub.2 --C(R.sub.13)(OH)--CH.sub.2 --COOR.sub.14 (gp. a), --Q--CH.sub.2 --C(R.sub.13)(OH)--CH.sub.2 --COOR.sub.14 (gp. c) or a gp. of formula (b): ##STR19##
Q=CO or --C(OR.sub.15).sub.2 --;
R.sub.15 =primary or sec. alkyl; each R.sub.15 being the same;
or R.sub.15 +R.sub.15 =(CH.sub.2).sub.2 or (CH.sub.2).sub.3 ;
R.sub.13 =H or 1-3C alkyl;
R.sub.14 =H, R.sub.16 or M;
R.sub.16 =ester gp.;
M=cation;
provided that Z may be gp. (c) only when X is CH.dbd.CH or CH.sub.2 --CH.dbd.CH and/or when R.sub.13 =1-3C alkyl;
R.sub.4, R.sub.7 and R.sub.10 =1-3C alkyl, n-, i- or t-butyl, 1-3C alkoxy, n- or i-butoxy, CF3, F, Cl, Br, phenyl, phenoxy or benzyloxy;
R.sub.5, R.sub.8 and R.sub.11 =H, 1-3C alkyl, 1-3C alkoxy, CF.sub.3, F, Cl, Br, COOR.sub.17, N(R.sub.19).sub.2, phenoxy or benzyloxy;
R.sub.17 =H, R.sub.18 or M;
R.sub.18 =1-3C alkyl, n, i- or t-butyl or benzyl;
R.sub.19 =alkyl;
R.sub.6, R.sub.9 and R.sub.12 =H, 1-2C alkyl, 1-2C alkoxy, F or Cl; provided that
(1) not more than one substituent of each of gps. A, B and C is CF.sub.3, not more than one substituent of each of gps. A, B and C is phenoxy, and not more than one substituent of each of gps, A, B and C is benzyloxy;
(2) when Z is gp. (c; Q=C(OR.sub.15).sub.2), the compound is in free base form and either (i) R.sub.14 is R.sub.16 and each R.sub.17 is independently R.sub.18 or (ii) R.sub.14 is M and each R.sub.17 is independently R.sub.18 or M; and
(3) when R.sub.14 and/or at least one R.sub.17 is M, the compound is in free base form.
Unless otherwise stated, all "alkyl" gps. are 1-6C and do not contain an asymmetric C; and "cycloalkyl" has 3-7C.
WO 8603-488-A (Sandoz AG) discloses indene analogues of mevalolactone, useful as hypolipoproteinaemia and anti-atherosclerotic agents, in free acid form or in the form of an ester or delta-lactone or in salt form which have the formula ##STR20## R=H or primary or secondary 1-6C alkyl; R.sub.1 =primary or secondary 1-6C alkyl;
R.sub.2, R.sub.4 =H, 1-4C alkyl, 1-4C alkoxy (except t-butoxy), CF.sub.3, F, Cl, phenoxy or benzyloxy;
R.sub.3 and R.sub.5 =H, 1-3C alkyl, 1-3C alkoxy, CF.sub.3, F, Cl, phenoxy or benzyloxy;
R.sub.6 =H, 1-2C alkyl, 1-2C alkoxy, F or Cl;
provided that there may only be one each of CF.sub.3, phenoxy or benzyloxy on each of the phenyl and indene rings;
X=(CH.sub.2).sub.n or --(CH.sub.2).sub.q --CH.dbd.CH(CH.sub.2).sub.q --;
n=1-3;
both q's=0, or one is 0 and the other is 1;
Z=--Q--CH.sub.2 --C(R.sub.10)(OH)--CH.sub.2 COOH, in free acid form or in the form of an ester or delta-lactone or salt;
Q=CO, --C(OR.sub.7).sub.2 -- or CHOH;
R'.sub.7s =the same primary or secondary 1-6C alkyl, or together are (C.sub.2).sub.2 or (CH.sub.2).sub.3 ;
R.sub.10 =H or 1-3C alkyl;
provided that Q may be other than CHOH only when X is CH.dbd.CH or CH.sub.2 --CH.dbd.CH and/or R.sub.10 1-3C alkyl.
U.S. Pat. No. 4,647,576 to Hoefle et al (Warner Lambert) discloses new C- and N-substituted pyrrole(s), useful as hypolipidaemic and hypocholesterolaemic agents, which have the formula ##STR21## X=--CH.sub.2 --, --CH.sub.2 CH.sub.2 -- or --CH(CH.sub.3)CH.sub.2 --; R.sub.1 =1- or 2-naphthyl; cyclohexyl; norbornenyl; phenyl optionally substituted by F, Cl, OH, CF.sub.3, 1-4C alkyl, 1-4C alkoxy or 2-8C alkanoyloxy; 2-,3- or 4-pyridinyl or their N-oxides; or ##STR22## R.sub.5 =1-4C alkyl; hal=chloride, bromide or iodide;
R.sub.6 =H or 1-6C alkanoyl;
R.sub.7 =alkyl or phenyl optionally substituted by Cl, Br or 1-4C alkyl;
or R.sub.2 and R.sub.3 together=--(CH.sub.2)n--, --CH.sub.2 OCH.sub.2 --, --CON(R.sub.8)CO-- or --CON(R.sub.9)N(R.sub.10)CO--;
n=3 or 4;
R.sub.8 =H, 1-6C alkyl, phenyl or benzyl;
R.sub.9 and R.sub.10 =H, 1-4C alkyl or benzyl;
R.sub.4 =1-4C alkyl, cyclopropyl, cyclobutyl or CF.sub.3.
European patent application 0 221 025 Al (Sandoz AG) discloses heterocyclic analogs of mevalonolactone and derivatives thereof having the formula ##STR23## wherein
Ra is a group --X--Z, Rb is R.sub.2, Rc is R.sub.3, Rd is R.sub.4 and Y is a group ##STR24## or
Ra is R.sub.1, Rb is a group --X--Z, Rc is R.sub.2, Rd is R.sub.3 and Y is O, S or a group ##STR25##
R.sub.1, R.sub.2, R.sub.3 and R.sub.4 are C.sub.1-4 alkyl not containing an asymmetric carbon atom, C.sub.3-7 cycloalkyl or a ring ##STR26## or in the case of R.sub.3 and R.sub.4 additionally hydrogen or for R.sub.3 when Y is O or S ##STR27## whereby R.sub.17 is hydrogen or C.sub.1-3 alkyl and R.sub.18 and R.sub.19 are independently hydrogen, C.sub.1-3 alkyl or phenyl; each R.sub.5 is independently hydrogen, C.sub.1-3 alkyl, n-butyl, i-butyl, t-butyl, C.sub.1-3 alkoxy, n-butoxy, i-butoxy, trifluoromethyl, fluoro, chloro, bromo, phenyl, phenoxy or benzyloxy; each R.sub.6 is independently hydrogen, C.sub.1-3 alkyl, C.sub.1-3 alkoxy, trifluoromethyl, fluoro, chloro, bromo, phenoxy or benzyloxy and each R.sub.7 is independently hydrogen, C.sub.1-2 alkyl, C.sub.1-2 alkoxy, fluoro or chloro with the proviso that there may only be one each of trifluoromethyl, phenoxy or benzyloxy in each ring A present. X is (CH.sub.2).sub.m or (CH.sub.2).sub.q CH.dbd.CH(CH.sub.2).sub.q, m is 0, 1, 2 or 3 and both q's are 0 or one is 0 and the other is 1. ##STR28##
wherein R.sub.9 is hydrogen or C.sub.1-3 alkyl, in free acid form or in the form of an ester of .beta.-lactone thereof or in salt form as appropriate which compounds are indicated for use as hypolipoproteinemic and anti-atherosclerotic agents.
Tetrahedron Letters, 29, 929, 1988, discloses the synthesis of a 3-hydroxy-3-methyl-glutaryl coenzyme A reductase inhibitor of the structure ##STR29## where R is Na or C.sub.2 H.sub.5.
European patent application 127,848-A (Merck & Co, Inc.) discloses derivatives of 3-hydroxy-5-thia-.omega.-aryl-alkanoic acids having the structural formula: ##STR30## wherein Z is: ##STR31## n is 0, 1 or 2; E is --CH.sub.2 --, --CH.sub.2 --CH.sub.2 --, --CH.sub.2 --CH.sub.2 --Ch.sub.2 --, --CH.dbd.CH--CH.sub.2 --; or --CH.sub.2 --CH.dbd.CH--;
R.sub.1, R.sub.2 and R.sub.3 are, e.g., hydrogen, chloro, bromo, fluoro, C.sub.1 -alkyl, phenyl, substituted phenyl or OR.sub.7 in which R.sub.7 is, e.g., hydrogen,
C.sub.2-8 alkanoyl, benzoyl, phenyl, substituted phenyl, C.sub.1-9 alkyl, cinnamyl, C.sub.1-4 haloalkyl, allyl, cycloalkyl-C.sub.1-3 alkyl, adamantyl-C.sub.1-3 -alkyl, or phenyl C.sub.1-3 alkyl;
R.sup.4, R.sup.5 and R.sup.6 are hydrogen, chloro, bromo, fluoro or C.sub.1-3 alkyl; and
X is, e.g., hydrogen, C.sub.1-3 alkyl, a cation derived from an alkali metal or is ammonium.
Those compounds have antihypercholesterolemic activity by virtue of their ability to inhibit 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase and antifungal activity.
French patent application 2,596,393 A filed on Apr. 1, 1986 (Sanofi SA) discloses 3-carboxy-2-hydroxy-propane-phosphonic acid derivatives including salts thereof which are useful as hypolipaemic agents and have the formula: ##STR32## wherein R.sub.1 and R.sub.2 =H, lower alkyl or optionally substituted aralkyl;
R.sub.3 and R.sub.4 =H, lower alkyl or optionally substituted aryl or aralkyl.
These compounds are disclosed as giving greater reductions in cholesterol, triglyceride and phospholipid levels than meglutol.
European patent application 142,146-A (Merck & Co., Inc) discloses mevinolin-like compounds of the structural formula: ##STR33## wherein: R.sup.1 is, e.g., hydrogen or C.sub.1-4 alkyl;
These compounds are HMG-CoA reductase inhibitors.
British Patent 2205838 discloses HMG CoA reductase inhibitors which have the formula ##STR38## wherein R is OH or lower alkoxy; R.sup.x is H or lower alkyl;
and including pharmaceutically acceptable salts thereof.
Examples of hydrophobic anchors which are included in this copending application include ##STR39## wherein the dotted lines represent optional double bonds, wherein R.sup.1, R.sup.2, R.sup.2a and R.sup.2b may be the same or different and are each independently selected from H, halogen, lower alkyl, haloalkyl, phenyl, substituted phenyl or OR.sup.y wherein R.sup.y is H, alkanoyl, benzoyl, phenyl, halophenyl, phenyl-lower alkyl, lower alkyl, cinnamyl, haloalkyl, allyl, cycloalkyl-lower alkyl, adamantyl-lower alkyl or substituted phenyl-lower alkyl. Where Z is ##STR40##
R.sup.5 and R.sup.5' are the same or different and are H, lower alkyl or OH; ##STR41##
R.sup.6a is lower alkyl, hydroxy, oxo or halogen; q is 0, 1, 2 or 3, and
R.sup.7 is H or lower alkyl.
Where Z is ##STR42## one of R.sup.3 and R.sup.4 is ##STR43## and the other is lower alkyl, cycloalkyl or phenyl--(CH.sub.2).sub.p --, p is 0, 1, 2, 3 or 4;
wherein R.sup.13 is hydrogen, lower alkyl, lower alkoxy, (except t-butoxy), halogen, phenoxy or benzyloxy;
R.sup.14 is hydrogen, lower alkyl, lower alkoxy, halogen, phenoxy or benzyloxy;
R.sup.14a is hydrogen, lower alkyl, lower alkoxy, or halogen; and
with the provisos that both R.sup.14 and R.sup.14a must be hydrogen when R.sup.13 is hydrogen, R.sup.14a must be hydrogen when R.sup.14 is hydrogen, not more than one of R.sup.13 and R.sup.14 is trifluoromethyl, not more than one of R.sup.13 and R.sup.14 is phenoxy and not more than one of R.sup.13 and R.sup.14 is benzyloxy;
R.sup.8 is hydrogen, C.sub.1-4 alkyl, C.sub.3-6 cycloalkyl, C.sub.1-4 alkoxy (except t-butoxy), trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy;
R.sup.9 is hydrogen, C.sub.1-3 alkyl, C.sub.1-3 alkoxy, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy, with the provisos that R.sup.9 must be hydrogen when R.sup.8 is hydrogen, not more than one of R.sup.8 and R.sup.9 is trifluoromethyl, not more than one of R.sup.8 and R.sup.9 is phenoxy, and not more than one of R.sup.8 and R.sup.9 is benzyloxy.
R.sup.10 and R.sub.11 are independently selected from hydrogen, alkyl, cycloalkyl, adamantyl-1 or ##STR44## where R.sup.13, R.sup.14 and R.sup.14a are as defined above and q=0, 1, 2, 3 or 4.
Y is O, S or N-R.sup.10.
Where Z is ##STR45##
R.sup.a is H or primary or secondary 1-6C alkyl;
R.sup.b is primary or secondary 1-6C alkyl;
or R.sup.a +R.sup.b is (CH.sub.2).sub.r or (cis)--CH.sub.2 --CH.dbd.CH--CH.sub.2 ;
r=2, 3, 4, 5 or 6;
R.sup.12 is lower alkyl, cycloalkyl or ##STR46## wherein R.sup.8, R.sup.9, R.sup.13, R.sup.14 and R.sup.14a are as defined above.
When Z is ##STR47##
R.sup.15 and R.sup.16 are both H, Cl, Br, CN, CF.sub.3, phenyl, 1-4C alkyl, 2-8C alkoxycarbonyl, --CH.sub.2 OR.sup.17 or --CH.sub.2 OCONHR.sup.18 ;
R.sup.17 is H or 1-6C alkanoyl;
R.sup.18 is alkyl or phenyl optionally substituted by F, Cl, Br or 1-4C alkyl;
or R.sup.15 and R.sup.16 taken together are --(CH.sub.2).sub.s --, --CH.sub.2 OCH.sub.2 --, --CON(R.sup.19)CO--, or --CON(R.sup.20)N(R.sup.21)CO--;
s=3 or 4;
R.sup.19 =H, 1-6C alkyl, phenyl or benzyl;
R.sup.20 and R.sup.21 are H, 1-4C alkyl or benzyl;
with the added proviso that when Z is ##STR48## X can only be --CH.sub.2 --, --CH.sub.2 CH.sub.2 -- or --CH.sub.2 CH.sub.2 CH.sub.2.
Where Z is ##STR49##
R.sup.22 is lower alkyl, cycloalkyl, adamantyl-1 or ##STR50##
t=1, 2, 3 or 4;
R.sup.23 and R.sup.23a are the same or different and are each independently selected from hydrogen, lower alkyl, lower alkoxyl (except t-butoxy), halogen, phenoxy or benzyloxy; and
with the provisos that R.sup.23a must be hydrogen when R.sup.23 is hydrogen, not more than one of R.sup.23 and R.sup.23a is trifluoromethyl, not more than one of R.sup.23 and R.sup.23a is phenoxy, and not more than one of R.sup.23 and R.sup.23a is benzyloxy.
Where X is --CH.sub.2 O-- (carbon attached to P and O attached to Z), the hydrophobic anchor Z will be a phenyl or naphthalene type anchor such as ##STR51##
International Publication No. WO 88/01997 (PCT/EP87/00511) published Mar. 24, 1988, filed by Sandoz on behalf of Anderson et al discloses aza-indole and indolizine derivatives which are useful as hypolipoproteinaemic and antiatherosclerotic agents and have the formula ##STR52## wherein:
either one of Y.sup.1 -Y.sup.4 is --N--, and the others are --CH-- ##STR53##
and R.sub.10 and R.sub.15, and R.sub.11 and R.sub.14 form bonds R.sub.1 is a primary or secondary C.sub.1-6 alkyl, not containing an asymmetric carbon atom; R.sub.2 is a) ##STR54##
b) a primary or secondary C.sub.1-6 alkyl, not containing an asymmetric carbon atom
c) C.sub.3-6 cycloalkyl
or d) phenyl-(CH.sub.2).sub.m -- wherein R.sub.5 is hydrogen, C.sub.1-3 alkyl, n-butyl, i-butyl t-butyl,
C.sub.1-3 alkoxy, n-butoxy, i-butoxy, trifluoromethyl fluoro, chloro, phenoxy or benzyloxy;
R.sub.6 is hydrogen, C.sub.1-3 alkyl, C.sub.1-3 alkoxy, fluoro, chloro, trifluoromethyl, phenoxy or benzyloxy;
R.sub.7 is hydrogen, C.sub.1-2 alkyl, C.sub.1-2 alkoxy, fluoro or chloro;
m is 1, 2 or 3; with the proviso that not more than one of R.sub.5 and R.sub.6 is trifluoromethyl, not more than one of R.sub.5 and R.sub.6 is phenoxy, and not more than one of R.sub.5 and R.sub.6 is benzyloxy; ##STR55##
and R.sub.14 and R.sub.15, and R.sub.10 and R.sub.11 form bonds; each of R.sub.1 and R.sub.2 is, independently, as defined under R.sub.2 above, and R.sub.2 may additionally be hydrogen: ##STR56## wherein n is 1, 2 or 3 ##STR57## and in which R.sub.8 is hydrogen, R.sub.9 or M, wherein R.sub.9 is a physiologically acceptable and hydrolysable ester group, and M is a pharmaceutically acceptable cation.